Project Summary/Abstract Multiple sclerosis (MS) is a debilitating, immune-mediated neurological disease that typically affects young adults, with higher frequency in women. In this disease immune cells target and destroy myelin in the central nervous system (CNS) causing demyelination and thus neurological alterations. There is no known cure for MS and many of the current treatments are not specific and suppress the function of the entire immune system. There is a great interest in development of novel, more specific and more effective therapies for MS. We developed a new therapy, which shows high efficiency in the treatment of Experimental Autoimmune Encephalomyelitis (EAE), the mouse model for MS, in a semitherapeutic setup. The treatment is based on delivery of specific myelin antigens and tolerogenic factors encapsulated in the FDA-approved poly(lactic-co- glycolic acid) (PLGA) microparticles (MPs) for controlled intracellular delivery through phagocytosable MPs, as well as for controlled delivery to surface receptors through non-phagocytosable MPs, thus constituting a dual MP system (dMP). The treatment is specific, being dependent on the specific myelin antigens, as MPs loaded with an irrelevant peptide did not block the disease. In addition, EAE blocking was dependent on encapsulation of the treating drugs, as soluble factors and empty particles were not effective in the treatment. We hypothesize that the therapeutic success translated in blocking of EAE by the dMP treatment is a consequence of tolerance induction. We thus propose to establish the mechanisms by which the dMP treatment blocks EAE. Additionally, we propose to test the dMP treatment in advanced stages of EAE, as well as in a remission/relapsing model and further optimize the regimen of treatment. The proposed studies in this application are of the highest significance, given its specificity and the fact that the therapeutic options for MS are limited and many of them lack the needed specificity.